Project Summary/Abstract Osteoarthritis (OA) is a prevalent musculoskeletal disease characterized by local, low-grade inflammation in the affected joints. Inflammation in OA modulates both local and higher-order neuroplasticity through decreased innervation in the inflamed synovium and lowered thresholds of dorsal horn neurons, respectively. Dysregulation of the autonomic nervous system (ANS) has been considered in the initiation and progression of other inflammatory and chronic pain disorders such as rheumatoid arthritis, but has not been explored in OA. However, my preliminary data demonstrate widespread ANS dysregulation in a surgical rat knee OA model 8-10 weeks after initiation. Unfortunately, autonomic dysfunction related to the pathophysiologic and symptomatic progression of knee OA is not well understood. Pain is the cardinal symptom of OA. In early stages of the disease, pain arises with use of the joint, indicating a nociceptive component. In nave animals, nociceptive afferent feedback from the periphery interacts bi- directionally with the ANS. For example, stimulation of the nucleus tractus solitaries inhibits nociceptive signal transmission while nociceptive feedback attenuates the parasympathetic nervous system by damping vagal activity. However, these autonomic-nociceptive relationships have not been explored in the knee joint. To address these gaps, the central goal of this proposal is to close the gap between nociception at the knee and vagal nerve activation and to investigate the role of nociception and the ANS in symptomatic and pathophysiologic progression of OA. In Aim 1, I the joint-brain axis will be investigated by quantifying vagal nerve response to acute nociceptive knee stimulations. In Aim 2, shifts in vagal nerve response due to chronic progression of OA pain and inflammation in the rat will be quantified. This expands on Aim 1 to correlate pain- related gait compensations and pathologic joint damage to shifts in vagal nerve responses. Because OA is a heterogeneous disease with varied mechanisms of onset and severity of symptoms, two models of OA will be investigated. This research is significant and innovative because it will provide the first quantitative evidence of parasympathetic changes in rodent models of OA. Specifically, vagal output in response to nociceptive sensory stimuli will be quantified to establish the presence of the autonomic joint-brain axis. Shifts in these responses will be assessed alongside pain-related behavioral changes in rodent models of OA to evidence a role for the autonomic nervous system in OA symptomatic progression. This proposal will utilize specialized quantitative techniques to understand novel mechanisms contributing to OA pain and disability, thereby becoming among the first studies to elucidate the role of the ANS in OA pathogenesis and OA symptom progression.